Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer
Treatment for advanced gastric cancer is challenging. Epidermal growth factor receptor (EGFR) contributes to the proliferation and development of gastric cancer (GC), and its overexpression is associated with unfavorable prognosis in GC. Cetuximab, a monoclonal antibody targeting EGFR, failed to imp...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2021-09-01
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| Series: | Integrative Cancer Therapies |
| Online Access: | https://doi.org/10.1177/15347354211045349 |
| _version_ | 1826902116256448512 |
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| author | Huanrong Ma PhD Jingjing Wu Bachelor Minyu Zhou PhD Jianhua Wu PhD Zhenzhen Wu PhD Li Lin PhD Na Huang PhD Wangjun Liao PhD Li Sun PhD |
| author_facet | Huanrong Ma PhD Jingjing Wu Bachelor Minyu Zhou PhD Jianhua Wu PhD Zhenzhen Wu PhD Li Lin PhD Na Huang PhD Wangjun Liao PhD Li Sun PhD |
| author_sort | Huanrong Ma PhD |
| collection | DOAJ |
| description | Treatment for advanced gastric cancer is challenging. Epidermal growth factor receptor (EGFR) contributes to the proliferation and development of gastric cancer (GC), and its overexpression is associated with unfavorable prognosis in GC. Cetuximab, a monoclonal antibody targeting EGFR, failed to improve the overall survival of gastric cancer patients indicated in phase III randomized trials. Glutamine is a vital nutrient for tumor growth and its metabolism contributes to therapeutic resistance, making glutamine uptake an attractive target for cancer treatment. The aim of the present study was to investigate whether intervention of glutamine uptake could improve the effect of cetuximab on GC. The results of MTT assay showed that by glutamine deprivation or inhibition of glutamine uptake, the viability of gastric carcinoma cells was inhibited more severely than that of human immortal gastric mucosa epithelial cells (GES-1). The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l -γ-glutamyl- p -nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo . Moreover, combining cetuximab and GPNA induced cell apoptosis considerably in gastric carcinoma cells, as shown by flow cytometry, and had a higher depressing effect on gastric cancer proliferation both in vitro and in vivo , as compared to either treatment alone. The present study suggested that inhibition of glutamine uptake may be a promising strategy for improving the inhibitory efficacy of cetuximab on advanced gastric cancer. |
| first_indexed | 2024-12-17T12:48:42Z |
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| id | doaj.art-131b8c1bcefb452da6ebcacd9c488d8f |
| institution | Directory Open Access Journal |
| issn | 1552-695X |
| language | English |
| last_indexed | 2025-02-17T07:34:38Z |
| publishDate | 2021-09-01 |
| publisher | SAGE Publishing |
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| series | Integrative Cancer Therapies |
| spelling | doaj.art-131b8c1bcefb452da6ebcacd9c488d8f2025-01-03T11:03:39ZengSAGE PublishingIntegrative Cancer Therapies1552-695X2021-09-012010.1177/15347354211045349Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric CancerHuanrong Ma PhD0Jingjing Wu Bachelor1Minyu Zhou PhD2Jianhua Wu PhD3Zhenzhen Wu PhD4Li Lin PhD5Na Huang PhD6Wangjun Liao PhD7Li Sun PhD8Southern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaSouthern Medical University, Guangzhou, P.R. ChinaTreatment for advanced gastric cancer is challenging. Epidermal growth factor receptor (EGFR) contributes to the proliferation and development of gastric cancer (GC), and its overexpression is associated with unfavorable prognosis in GC. Cetuximab, a monoclonal antibody targeting EGFR, failed to improve the overall survival of gastric cancer patients indicated in phase III randomized trials. Glutamine is a vital nutrient for tumor growth and its metabolism contributes to therapeutic resistance, making glutamine uptake an attractive target for cancer treatment. The aim of the present study was to investigate whether intervention of glutamine uptake could improve the effect of cetuximab on GC. The results of MTT assay showed that by glutamine deprivation or inhibition of glutamine uptake, the viability of gastric carcinoma cells was inhibited more severely than that of human immortal gastric mucosa epithelial cells (GES-1). The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l -γ-glutamyl- p -nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo . Moreover, combining cetuximab and GPNA induced cell apoptosis considerably in gastric carcinoma cells, as shown by flow cytometry, and had a higher depressing effect on gastric cancer proliferation both in vitro and in vivo , as compared to either treatment alone. The present study suggested that inhibition of glutamine uptake may be a promising strategy for improving the inhibitory efficacy of cetuximab on advanced gastric cancer.https://doi.org/10.1177/15347354211045349 |
| spellingShingle | Huanrong Ma PhD Jingjing Wu Bachelor Minyu Zhou PhD Jianhua Wu PhD Zhenzhen Wu PhD Li Lin PhD Na Huang PhD Wangjun Liao PhD Li Sun PhD Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer Integrative Cancer Therapies |
| title | Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer |
| title_full | Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer |
| title_fullStr | Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer |
| title_full_unstemmed | Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer |
| title_short | Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer |
| title_sort | inhibition of glutamine uptake improves the efficacy of cetuximab on gastric cancer |
| url | https://doi.org/10.1177/15347354211045349 |
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